As many as 50% of HIV infected patients develop HIV-associated neurocognitive disorder (HAND), despite treatment with antiretroviral therapy (ART). The number of affected patients may rise, given the increasing, and nearly normal, life expectancy of HIV patients. Fluctuating and sometimes declining neuropsychological performance in treated HIV patients are clinically significant because they may lead to decreased adherence to medication, higher mortality, poorer quality of life and mental health issues. The etiologies of these progressive neuropsychological changes are unclear, but may reflect dysfunction in a range of neural subsystems, including cortico-cortical, cortico-cerebellar or corticostriatal circuits that serve to integrate cognitive, motor and affective processing mechanisms. To study neuropsychological effects of HIV infection and its co-morbidities, we propose to differentiate HIV effects from five critical confounding factors: age, hepatitis C co-infection, ART type, systemic inflammation, and vascular risk. We will determine: (1) if multiple, compared to single, clinical and neuroimaging features can predict subsequent neuropsychological performance and (2) if longitudinal changes in brain structure and function provide evidence about the nature of the underlying neural mechanisms of observed performance changes. Using a Research Domain Criteria (RDoC) framework, we will focus on integrating performance measures from the cognitive and sensorimotor domains with underlying changes in brain structure and function. We are fortunate to have access to longitudinal data from the MACS, now known as the MACS/WIHS Combined Cohort Study, a large, well characterized sample of males and females that will allow us to identify changes in brain structure and function during HIV treatment. The research is significant because neuropsychological performance deficits remain prevalent in spite of widespread ART use and have significant public health implications. This project will allow identification of HIV patients who may benefit from medical care changes related to vascular risk or ART type. The Principal Investigator, Erin O?Connor MD, is an Assistant Professor of Radiology at UMSOM, whose long term career goal is to become an independent investigator in translational neuroradiology, focusing on imaging predictors of neuropsychological effects in neuroinflammatory, neurodegenerative and neurovascular disorders. To work towards this goal, we propose a research project designed to identify the neural mechanisms underlying HIV-related cognitive and motor disability. For this project, Dr. O?Connor will be mentored by a highly experienced neuroimaging team, including Dr. Chang, an HIV expert, Dr. Becker, an expert in HIV neuropsychology and aging, and Dr. Zeffiro, an expert in translational neuroimaging and statistics. The skills and analyses derived from this training grant will serve as the basis for a subsequent R01 proposal designed to validate predictors of neuropsychological change in treated HIV patients.